SPID#: 15 This study is designed to identify virus-host interactions that correlate with the absence of SIV pathogenesis in sooty mangabeys compared with rhesus macaques that develop simian AIDS after experimental infection. During this reporting period, 14 of 14 naturally infected sooty mangabeys were found to have a high level of plasma viremia using a SIVsmm specific QC-PCR assay developed in this laboratory. Viremia could not be detected in two seronegative mangabeys using assay conditions capable of detecting as few as 640 SIV RNA copies/ml. There was no evidence for SIV-specific CTL activity in 3 mangabeys with high level viremia using conditions that readily detect anti-SIV CTL activity in rhesus macaques (ie prestimulation with autologous B cell lines expressing SIV antigens after infection with recombinant vaccinia). These findings suggest that greater immune control of viral replication does not explain the lack of SIV pathogenesis in mangabeys. Analysis of SIVsmm env diversity using RNA based heteroduplex mobility assays and direct sequence comparisons indicated that SIV populations in mangabeys are highly diverse. Mangabeys with higher levels of viremia had more diverse virus populations suggesting that random genetic drift, or weak humoral immune selection of structurally unconstrained viral epitopes, were the primary determinants of SIV env diversification in mangabeys. Development of methods for experimental infection of sooty mangabeys were initiated late in the reporting period. One sooty mangabey and one rhesus macaque were intravenously challenged with a common stock of SIVmac239/open nef. Viral replication was attentuated in the mangabey even at early time points (eg:day 2 post-infection) suggesting decreased viral tropism for the mangabey host. Lymphocyte immunophenotyping indicated a surge in CD8 cell activation in the macaque, but not in the mangabey, suggesting that virus-induced cell proliferation may have enhanced viral load in the macaque. Anti-SIV CTL responses were evident in both animals. The strong CTL response in the experimentally infected mangabey differs from the absent or low level CTL activity in naturally infected mangabeys and suggests that the conditions of SIV challenge may affect the induction of cell mediated immune tolerance in mangabeys. Methods of experimental infection will be developed in the coming year to determine the timing and duration of CTL responses after experimental challenge with stocks of SIV derived directly from mangabeys.